THE FETAL BASIS OF ADULT DISEASE: ROLE OF THE ENVIRONMENT

RELEASE DATE:  May 14, 2004

PA NUMBER:  PAR-04-104

EXPIRATION DATE:  August 13, 2004, unless reissued.

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institute of Health (NIH)
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Environmental Health Sciences (NIEHS)
 (http://www.niehs.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.113, 93.114 

LETTER OF INTENT RECEIPT DATE: July 10, 2004  
APPLICATION RECEIPT DATE: August 12, 2004

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THE PA

This PA replaces PAR-03-121.

It is recognized that between two-percent and five-percent of all live-born 
infants have a major developmental defect.  Approximately 40 percent of these 
defects are thought to be due to the effect(s) of an adverse exposure of a 
genetically pre-disposed fetus to intra-uterine environmental factors.  It is 
now clear that in many cases the fetus is more sensitive than the adult to 
the same environmental insults.  Exposure to environmental agents during 
early development can result in death, structural malformation, and/or 
functional alteration of the embryo/fetus.  These toxicant-induced pathogenic 
responses are most likely the result of altered gene expression associated 
with altered cell production and cell differentiation involved in the 
establishment of cell lineages leading to the structural and functional 
character of the tissues, organs, and systems that arise from these lineages.

The NIEHS has a significant program that addresses the role of developmental 
exposures on structural malformations i.e., classical birth defects and on 
functional alterations whose effects are readily observable early in 
development.  The purpose of this program announcement with a set aside of 
funds and a Special Emphasis Panel review by the NIH Center for Scientific 
Review is to stimulate research in an important and emerging area of 
developmental toxicology: the effects of in utero exposures that cause 
permanent functional changes that are not overtly, grossly teratogenic yet 
that result in increased susceptibility to disease/dysfunction later in the 
life span.  This program announcement seeks to encourage the application of 
the new high-throughput functional-genomic, metabonomic, proteomic, and 
bioinformatic technologies to pursue an understanding of these latent effects 
of in utero environmental insult.

RESEARCH OBJECTIVES

The underlying scientific hypothesis behind the fetal basis of adult diseases 
has been developed by epidemiology studies and emphasized by Dr. David Barker 
in the United Kingdom.  Most of the supporting studies in this area have 
concentrated on grossly altered nutrition in utero and its striking influence 
on multiple aspects of adult health and disease risk.  Dr. Barker has shown 
that during development fetuses respond to severe malnutrition by favoring 
the metabolic demands of the growing brain/CNS and heart at the expense of 
other tissues.  The growing brain/CNS and heart tissue may not, however, 
escape entirely unscathed.  The long-term consequences of this response are 
that the fetus is protected from death, is live-born, but is more prone to 
diseases later in life.  In support of the Barker hypothesis, epidemiology 
studies have shown that markers of malnutrition, such as low birth weight, 
small for gestation age, frank intra-uterine growth retardation (IUGR) or 
clinically abnormal thinness at birth strongly predicts the subsequent 
occurrence of hypertension, hyperlipidemia, insulin resistance, type 2 
diabetes, ischemic heart disease, breast cancer or prostate cancer in adult 
life.  Fetuses that are clinically malnourished during the first trimester of 
development are three times more likely to be obese as adults.  In addition 
to malnutrition, environmental exposures present during in utero development 
can have profound influences on fetal growth.  Evidence has been presented in 
human populations that gross, heavy exposure to PM10 air pollution containing 
carcinogenic PAHs can be correlated with increased IUGR with a peak impact in 
the earlier portion of the first trimester – a most vulnerable period of the 
cell lineage expansion, differentiation, and cell interaction events of 
organogenesis and first growth. 

The concept of fetal programming of structural-functional formations during 
development has been proposed to explain these findings and the resultant 
research area is referred to as "Fetal Basis of Adult Disease" (FeBAD) 
research. "Programming" is the term used to describe lifelong changes in 
function that follow a particular event in an earlier period of the life 
span.  While epidemiology studies have identified the phenomenon of metabolic 
programming, little is known about the mechanism(s) by which fetal insults 
lead to altered programming and to disease later in life.  In addition, 
emphasis thus far has been on alterations in nutrition during development 
with virtually no focus on the role that exposures to environmental agents, 
such as air or water pollution, either alone or in combination with 
qualitative alterations in macro- or micro-nutrition (i.e. soy protein, 
phytoestrogens, isoflavones or other chemicals in herbal supplements or 
dietary sources), might have on this phenomenon.

There is, however, evidence that some environmental agents, especially those 
with endocrine agonist or antagonist activity, may alter developmental 
programming via alteration in gene expression or gene imprinting that do not 
result in malformations but in functional deficits that do not become 
apparent until later in life.  In the reproductive tract, the classic example 
of this phenomenon in the environmental area is the diethylstilbestrol (DES) 
story.  In humans, in utero exposure to DES leads to an increase in vaginal 
adenocarcinoma around the time of puberty.  In mice, neonatal DES exposure 
leads to an increase in uterine adenocarcinoma in adulthood.  While the 
direct connection has not been made between in utero programming changes due 
to DES and later life disease, it is known that DES (in the animal studies) 
results in altered gene expression in the uterus that is irreversible without 
any noticeable gross alterations in uterine morphology.  Other examples in 
the reproductive area include developmental exposures of the monkey to 
androgens that lead to polycystic ovary syndrome-like effects in the adult, 
data (still considered controversial) showing that environmental estrogens, 
such as DES, methoxychlor and bisphenol A, cause alterations in gene 
expression in the rat prostate that are irreversible and are correlated with 
increased prostate cancer, and data showing a link between in utero exposure 
to dioxin and endometriosis later in life in primates and rodents.

Cardiopulmonary diseases in postnatal life have also been linked to prenatal 
exposure.  The most well-known example is the association between low birth 
weight (which is associated with poor maternal nutrition and perhaps 
corticosteroid exposure) and cardiovascular disease (e.g., myocardial 
infarcts) and predictors of future cardiovascular disease, such as 
hypertension and atherosclerosis, and complex metabolic disease, such as 
diabetes.  In addition, studies have shown that maternal smoking is 
associated with deficits in lung function and with asthma symptoms in the 
offspring.  Data indicate that these associations are independent of smoking 
status after birth.

Some forms of neurodegenerative disease may have their origins in in utero 
exposures.  For example, there is preliminary evidence that a bacterial 
stimulus (endotoxin) can produce cytokines that impair the development of the 
mesencephalic dopaminergic systems during pregnancy.  This attenuation of the 
dopamine neurons during fetal development leaves the offspring with fewer 
dopaminergic neurons at birth and at possible increased risk for Parkinson's 
disease in later life.  In a similar vein, there is preliminary evidence that 
exposure to environmental neurotoxins during dopaminergic development 
enhances the susceptibility to accelerated dopaminergic cell death during 
aging via the common molecular mechanism(s) of the alteration of stress-
activated signal transduction pathways, expression of differentiation 
transcription factors, survival factors or phenotype marker proteins in the 
nigral dopaminergic neurons.  Similarly, there is evidence that in utero 
exposure to polycyclic biphenols (PCBs) leads to altered thyroid function and 
subsequent learning disabilities later in life.  In all instances data are 
needed to show that the in utero exposures actually lead to an altered 
programming at the molecular level and that the disease/dysfunction is a 
direct result, albeit, temporally discordant in its onset and/or progression, 
of that altered programming.

Another promising area for investigation is how environmental prenatal 
exposures might alter immune system programming.  The development of the 
immune system, including the development of the repertoire of reactive 
lymphocytes that will exist in postnatal life, begins prenatally.  
Alterations of the fetal immune environment might pre-program the highly 
sensitive fetal immune system for aberrant immune regulation, leading to a 
loss of tolerance to self-antigens and resulting in an increased risk for 
autoimmune disease.  These changes might manifest in adult life and perhaps 
only after a second exposure to related environmental chemicals.  There is 
evidence, for instance, that mice exposed prenatally to estrogenic compounds 
appear to develop normal immune systems.  However, when stimulated with 
certain environmental chemicals, they can show an increased susceptibility to 
autoimmune disease.  Similarly, there is evidence in humans and experimental 
animals that prenatal exposure to immunosuppressive drugs can lead to immune 
alterations in the mature animals, including development of autoantibodies 
and a higher risk of autoimmune disease in susceptible animals.

Obesity is a disease whose prevalence has risen dramatically in developed 
countries over the past two-to-three decades reaching epidemic proportions in 
the United States.  It is mainly considered to be caused by overeating and 
lack of physical activity on a background of genetic predisposition.  The 
major environmental influence on obesity thus has been in utero and postnatal 
nutrition.  A large number of epidemiological studies have demonstrated a 
direct relationship between birth weight and body mass index attained later 
in life.  Indeed the data support the seeming paradox of increased adult 
adiposity associated with both ends of the birth weight spectrum: higher body 
mass index with higher birth weight and increased central adiposity with 
lower birth weight.  Recent data support the hypothesis that nutrition is not 
the only environmental influence that may have an effect on obesity.  There 
is increasing evidence that in utero exposure to environmental chemicals at 
environmentally relevant concentrations may alter developmental programming 
of adipose tissue and/or gastrointestinal-hypothalamic centers via 
irreversible alterations in tissue specific function as a result of altered 
gene expression.  The chemicals that appear to be the most likely candidates 
for altering in utero tissue function that may result in obesity later in 
life include environmental estrogens such as diethylstilbestrol and bisphenol 
A, as well as other estrogenic endocrine disruptors, such as dioxin and 
nicotine.  More data are needed to show proof-of-principle, not only with 
these chemicals.  In addition, the field needs to be expanded to determine 
which chemicals and chemical types could have an impact on adolescent and 
adult obesity via in utero exposure.
 
Based on the epidemiology data that support the Barker Hypothesis and the 
preliminary data showing alterations in gene expression and imprinting due to 
in utero exposures to some environmental agents, we propose that exposure to 
certain environmental chemicals as well as altered nutrition, or in 
combination with altered nutrition, will in some situations, not lead to 
easily identifiable structural malformations, but instead to alterations in 
developmental programming expressed as a permanently altered gland, organ or 
system potential.  These states of altered potential might be a result of 
changes in gene expression, due to altered imprinting, and the underlining 
methylation-related protein-DNA relationships associated with chromatin 
remodeling.  These effects may occur in a time specific (i.e., vulnerable 
window) and tissue-specific manner and such alterations may be irreversible.  
The end-result is an animal that is sensitized such that it will be more 
susceptible to diseases later in life.  The environmental insult could act 
via a one hit or two/three hit scenario.  That is, there could be an in utero 
exposure that would lead by itself to pathophysiology later in life or there 
could be in utero exposure combined with a neonatal exposure (same or 
different compound(s) or adult exposure that would trigger the 
pathophysiology.  The pathophysiology or functional change that results from 
the exposures/insult could lead to: a) the occurrence of a disease that 
otherwise would not have happened, b) an increase in risk for a disease that 
would normally be of lower prevalence, or c) either an earlier onset of a 
disease that would normally have occurred or an exacerbation of the disease.  
Finally, the pathophysiology could have a variable latent period from onset 
in the neonatal period, to early childhood, to pubertal, to early adulthood 
to late adulthood depending on the toxicant, time of exposure and 
tissue/organ affected and potentially transgenerational effects.

RESEARCH APPROACHES RELEVANT TO THIS PA

Note that this PA expands the areas of interest described in the previous 
FeBAD PAs (PAR-02-105 and PAR-03-121). In addition to the adult onset 
disorders/dysfunctions noted in the two previous FeBAD PAs, the study of 
diseases and dysfunctions of adolescence, including abnormal onset of 
puberty, will now be considered responsive.  

o To provide a sound mechanistic understanding of fetal programming of adult 
disease, studies supported by this initiative must involve whole animal 
developmental exposures during gestation.  Applicants can propose studies 
using transgenics, model organisms, or rodent models.  For the purpose of 
this initiative, human studies (clinical or epidemiology) are not responsive.

o Applicants must study an environmental agent/chemical/stressor to which 
there is human exposure and the potential for in utero exposure.  This can 
include any endocrine active chemical(s) or organic solvents, particulate 
matter (PM), pesticides, nutritional supplements, phytochemicals or metals.  
Nutrition alone cannot be used as an in utero exposure but can be studied in 
conjunction with another exposure.

o Applications must propose studies that focus on in utero exposures, but 
additional exposures at other time points (e.g., exposure beginning in utero 
and extending to postnatal period; exposure in utero followed by adult 
exposure) can be included.

o This initiative encourages the use of the new technologies of gene 
expression profiling, and where appropriate, the examination of epigenetics 
(methylation, imprinting, and chromatin remodeling) to understand the 
mechanism responsible for the increased susceptibility to disease as a result 
of in utero exposure.

o Applications must link in utero exposures to changes that are tissue 
specific and irreversible, such as changes in gene expression or methylation 
or changes in cell numbers, locations, or interactions, that will affect 
tissue function but are not considered teratogenic.  These changes will then 
need to be correlated with the diseases/dysfunction studied in the adult or 
adolescent animal.

o A specific adult or adolescent onset disease or dysfunction must be the 
focus of the application with emphasis on the role of in utero exposure and 
tissue specific changes in function in the fetus to the adolescent/adult 
onset or severity of the disease.  Applications that are not focused on a 
specific adolescent/adult disease or dysfunction are not responsive.  For 
example, applications that focus on in utero exposures as triggers of 
diseases of childhood are not responsive to this specific announcement.

o Applications must focus on one of the following five emphasis areas: the 
reproductive tract, the cardiopulmonary system, the brain/nervous system or 
the immune/autoimmune system and obesity.  Diseases of tissues or organ 
systems other than the five described here are not responsive to this 
specific announcement.  The diseases of special interest to NIEHS with 
respect to this initiative include reproductive/hormonal (fertility, 
endometriosis, fibroids, premature menopause, polycystic ovary syndrome, 
prostate/ovary/breast cancer, or early or late onset of puberty) 
cardiopulmonary (heart disease, atherosclerosis, hypertension, chronic 
obstructive pulmonary disease, adult asthma) and brain/CNS neurodegenerative 
diseases—Parkinson's, Alzheimer’s, immune/autoimmune (altered immune 
responsiveness, systemic or tissue specific autoimmune diseases of adulthood) 
and adolescent or adult obesity and related problems of metabolic syndrome 
and diabetes.  

It may be possible to submit applications to this initiative with an emphasis 
on other diseases as long as they are related to one or more of the above 
noted five emphasis areas.

o Applicants should be cognizant of the possible confounding effects of 
dietary components, especially phytoestrogens and other estrogenic 
components, when assessing all endpoints, but especially obesity.  
Consideration should be given to using synthetic diets and the chosen diet 
should be justified in relation to the possibility of confounding effects.

o Critical areas of expertise that are required of applicants include 
developmental biology/toxicology and disease pathophysiology.  Expertise in 
technologies such as gene expression profiling and proteomics (including data 
analysis and interpretation of global gene expression), epigenetics 
alterations, cell signaling, and signal transduction are strongly encouraged. 

MECHANISM(S) OF SUPPORT

This PA will use the NIH exploratory/developmental (R21) award mechanism.  As 
an applicant, you will be solely responsible for planning, directing and 
executing the proposed project.  The R21 grant award mechanism supports 
innovative, high-risk/high-impact research requiring preliminary testing or 
development; exploration of the use of approaches and concepts new to a 
particular substantive area; and research and development of data upon which 
significant future research may be built.  Applications will be considered 
high-impact if they demonstrate the potential for groundbreaking, precedent 
setting significance, and high-risk because they either lack sufficient 
preliminary data to ensure their feasibility, or involve the use of a new 
model system or technique.

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular budget format.  This program does 
not require cost sharing as defined in the current NIH Grants Policy 
Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm.

FUNDS AVAILABLE

It is anticipated that approximately $2 million in FY 2005 will be available 
to fund grants in response to this PA.  An applicant for an R21 grant may 
request a project period of up to three years and a budget for total direct 
costs, not including third party facilities and administrative costs, not to 
exceed $100,000 per year.  Applicants should include funds for a grantee 
meeting at NIEHS for each year of the award.
 
Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary.  Although the financial plans of the NIEHS provide 
support for this program, awards pursuant to this PA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your general questions or questions about scientific/research issues 
related to the cardiopulmonary or immune/autoimmune areas to:

J. Patrick Mastin, Ph.D.
Scientific Program Administrator
Chief, Cellular, Organ and Systems Pathobiology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (EC-23)
Research Triangle Park, NC 27709
Telephone: 919-541-3289
Fax: 919-541-5064
Email: mastin@niehs.nih.gov

o Direct your questions about scientific/research issues related to the 
reproductive/puberty/obesity areas to:

Jerry Heindel, Ph.D.
Scientific Program Administrator
Cellular, Organ and Systems Pathobiology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (EC-23)
Research Triangle Park, NC 27709
Telephone: 919-541-0781
Fax: 919-541-5064
Email: heindelj@niehs.nih.gov

o Direct your questions about scientific/research issues related to the 
neurodegenerative area to:

Cindy Lawler, Ph.D.
Scientific Program Administrator
Cellular, Organ and Systems Pathobiology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (EC-23)
Research Triangle Park, NC 27709
Telephone: 919-316-4671
Fax: 919-541-5064
Email: lawler@niehs.nih.gov

or 

Annette Kirshner, Ph.D.
Scientific Program Administrator
Cellular, Organ and Systems Pathobiology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (EC-23)
Research Triangle Park, NC 27709
Telephone: 919-541-0488
Fax: 919-541-5064
Email: kirshner@niehs.nih.gov
 
o Direct your questions about financial or grants management matters to:

Mr. Dwight Dolby
Grants Management Specialist
Grants Management Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (EC-22), 111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Telephone: 919-541-7824
Fax: 919-541-2860
Email: dolby@niehs.nih.gov

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this PA

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NIEHS staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

J. Patrick Mastin, Ph.D.
Scientific Program Administrator
Chief, Cellular, Organ and Systems Pathobiology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233 (EC-23), 111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Telephone: 919 541-3289
Fax: 919-541-5064
Email: mastin@niehs.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements.  The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/.  The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be checked.

Applicants should note that R21 applications have a page limitation of 15 
pages for the Research Plan.

APPLICATION RECEIPT DATE: Applications submitted in response to this program 
announcement will be accepted on August 12, 2004.

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by the receipt date of 
August 12, 2004.  The CSR will not accept any application in response to this 
PA that is essentially the same as one currently pending initial review 
unless the applicant withdraws the pending application.  The CSR will not 
accept any application that is essentially the same as one already reviewed.  
This does not preclude the submission of a substantial revision of an 
unfunded version of an application already reviewed, but such application 
must include an Introduction addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within eight weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Environmental Health 
Sciences Council.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 
application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 
forward.

SIGNIFICANCE: Does this study address an important problem?  If the aims of 
the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

INNOVATION: Does the project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR: Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?

For R21 applications, the above stated criteria will be reviewed but it will 
be noted that the R21 is a developmental/exploratory grant mechanism that is 
used for high risk/high impact projects to generate preliminary data to 
develop novel hypotheses.  Therefore, review standards for preliminary data 
and past performance are not applicable for this mechanism.

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL REVIEW CONSIDERATIONS

BUDGET: The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.  

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: July 10, 2004
Application Receipt Date: August 12, 2004
Peer Review Date: November 2004
Council Review: February 2005
Earliest Anticipated Start Date: April 2005

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. 

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). 

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution.  The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.  Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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Research (OER)
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